This invention is generally in the area of modulation wound repair using a peptide inducer of syndecan expression.
Complex cellular behaviors such as those resulting in wound repair are influenced by a variety of soluble growth factors, cytokines, and insoluble extracellular matrix components. To exert their effects, many of these effector molecules must bind to the heparan sulfate chains that are at the surface of nearly all adherent cells (Ruoslahti and Yamaguchi, Cell, 64:867 (1991)). For example, interaction with cell surface heparan sulfate is required for cells to respond to the growth factors FGF-2 (Rapraeger, et al., Science, 252:1705 (1991); Yayon, et al. Cell, 64:841 (1991)) and HB-EGF (Higashiyama, et al., J. Cell Bio., 122:933-940 (1993)), and to the matrix component fibronectin (Guan, et al. Cell Reg., 2:951 (1991); Woods, et al., Molec. Biol. Cell, 4:605 (1993)). Indeed, Guan, et al. (1991); Bernfield, et al., in Annu. Rev. Cell Biol., G. E. Palade, B. M. Alberts, J. A. Spudich, Eds. (Annual Reviews Inc., Palo Alto, Calif., 1992), 8:365-393); Jalkanen, et al., Trends in Glyco-science and Glycotech, 5:107 (1993); G. David, FASEB J., 7:0123 (1993); and A. C. Rapraeger, Curr. Opin. Cell Biol., 5:844 (1993)) have proposed that cell surface heparan sulfate, which is derived mostly from the four members of the syndecan family of transmembrane proteoglycans (G. David, et al., J. Cell Biol., 111:3165 (1990)), acts together with specific signaling receptors to mediate the cellular response to such effectors. Changes in the abundance of cell surface heparan sulfate probably regulates the action of these effector molecules, yet it is not known how the amount of heparan sulfate at the cell surface is controlled.
Cell surface heparan sulfate mediates the activity of several growth factors, extracellular matrix components, proteases and other cellular effectors involved in wound repair. Syndecan-1, a major transmembrane heparan sulfate proteoglycan, is induced transiently on mesenchymal cells during the repair of skin wounds. Accordingly, induction of syndecan-1 can influence this process. Syndecan-1 induction can trigger cellular behaviors such as proliferation and migration that are involved in wound repair due to its ability to bind and thus augment the action of heparin-binding growth factors, including FGF-2, HB-EGF, and PDGF-AB, each found in repairing wounds. Cell surface syndecan-1 can also bind fibronectin, thrombospondin, tenascin and the fibrillar collagens. Accordingly, its induction can contribute to the effects of these extracellular matrix components that are involved in wound repair. Thus, the induction of syndecan-1 by PR-39 may mediate growth factor responsiveness and the changes in cell proliferation, migration, and adhesion that must take place for wound repair to proceed.
The expression of syndecan-1 is highly regulated in vivo. In mature tissues, syndecan-1 is expressed on the surface of epithelial cells but not on the surface of mesenchymal cells (K. Hayashi, et al., J. Histochem. Cytochem., 35:1079 (1987)). However, during cutaneous wound repair in the mouse, syndecan-1 is lost from the surface of the epithelial cells migrating into the wound and is induced on the dermal endothelial cells and fibroblasts of the forming granulation tissue (K. Elenius, et al., J. Cell Biol., 114:585 (1991)). These changes resemble those occurring during embryonic tissue interactions: syndecan-1 is lost from epithelia undergoing changes in shape while it is induced on their associated mesenchymal cells (Trautman, et al., Development, 111:213 (1991)). Thus, in both wound repair and morphogenesis, situations that correspond with changes in expression of several potential ligands, including growth factors, matrix components, proteases and protease inhibitors, mesenchymal cells are induced to increase syndecan-1 at their surfaces.
It is therefore an object of the present invention to provide a method and means for modulating tissue repair and other cellular processes involving heparan sulfate binding to ligands through inducement of syndecan expression.
It is a further object of the present invention to provide methods and composition for modulating wound repair and healing in a cell specific manner.